While posttraumatic stress disorder (PTSD) is the fourth most common psychiatric disorder in the general U.S. population, a recent study reported that PTSD represents nearly half of all mental disorders for veterans of Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF). Most heavy drinkers among military personnel are less than 25 years old, and this same age group is reported to be at increased risk for PTSD and other mental health complications from combat deployment relative to veterans 40 years or older. Recent surveys of Naval, Marine, and Air Force recruits ages 18-20 report increased incidence of heavy/risky drinking during adolescence relative to the general U.S. Early adolescent onset of substance use is associated with increased risk of PTSD among other disorders. Because withdrawal from alcohol is accompanied by many of the same debilitating emotional symptoms seen in PTSD, we hypothesize that prior history of repeated alcohol intoxication and withdrawal during adolescence may directly increase vulnerability to onset of PTSD upon exposure to trauma due to alcohol-induced changes in brain circuits that mediate responses to stress. In Specific Aim 1, young adult male Wistar rats will be exposed to one of several conditions of social defeat stress (Nondefeat Control, 3x, 6x, or 9x defeat episodes) in the presence of a unique odor cue, followed by testing for signs of persistent PTSD-like behavioral and endocrine changes using the following paradigms: 1) elevated plus maze (anxiety-like behavior);2) acoustic startle reactivity (exaggerated startle);2) intracranial self-stimulation (ICSS) reward threshold deficits (anhedonia);4) plasma corticosterone (hypocortisolism). Avoidance of, and startle reactivity to, the trauma-associated odor cue also will be assessed. Specific Aim 2 will probe for any lasting consequences into young adulthood of varying history of intermittent ethanol vapor exposure (10 hr exposure per day on 1, 3 or 5 days/week, target blood alcohol levels of 200-300 mg/dL) during the periadolescent period (postnatal day 28-56), using these same behavioral and endocrine endpoints. Additional experiments in Aim 2 will then combine select periadolescent ethanol exposure conditions with select defeat parameters from Aim 1 to test our hypothesis of periadolescent ethanol-induced potentiation of the consequences of social defeat trauma. The prediction is that with increasing amount of adolescent alcohol exposure, fewer defeat episodes will be required to engender lasting behavioral and endocrine alterations, and/or the magnitude of alterations for a given number of defeat episodes will be greater. A further prediction is that corticotropin releasing factor (CRF) and/or norepinephrine (NE) systems in the CNS are central to the potentiative effects of ethanol exposure and withdrawal on PTSD vulnerability. Specific Aim 3 will examine whether systemically active CRF (e.g. MPZP) and NE (e.g. prazosin) antagonists can reverse PTSD-like consequences in the social defeat trauma model refined in Aim 1, and any observed alcohol-potentiated vulnerability to social defeat trauma from Aim 2. Further experiments in Aim 3 will explore whether prior alcohol history can potentiate the dose-response function for stress-like responses to stimulation of NE systems (with yohimbine) and/or CRF receptors (with CRF). If all Aims yield the expected results, this project will: 1) identify a prevalent putative environmental risk factor in the etiology of PTSD for OEF/OIF military personnel and returning veterans (i.e. adolescent alcohol);2) identify possible key CNS substrates (CRF, NE) of PTSD and alcohol-potentiated PTSD symptoms;3) develop and pharmacologically validate (MPZP, prazosin) a preclinical platform for testing potential pharmacotherapeutic interventions for treatment of PTSD and alcohol-potentiated PTSD symptoms;and 4) develop and validate (CRF, yohimbine) a preclinical model for identifying potential screening tools for enhanced traumatic stress vulnerability resulting from prior alcohol exposure. PUBLIC HEALTH RELEVANCE: Recent survey data indicate that heavy drinking is more prevalent in young military recruits (age 18-20) than in the general young adult population, and early adolescent onset of alcohol use/dependence is correlated with increased risk of mental disorders including posttraumatic stress disorder (PTSD). The goal of this project is to identify in an animal model any causal link between a adolescent alcohol exposure and increased risk of PTSD-like symptoms upon subsequent exposure to traumatic stress. Confirmation of such a causal link has translational implications for a potential environmental risk factor (prior alcohol abuse) in the etiology of PTSD for a significant percentage of OEF/OIF military personnel and returning veterans. Additional translational benefits for the VA patient population are expected to emerge from proposed pharmacological validation of the animal model as a preclinical tool for identification of a) novel treatments for PTSD;and b) screening tools for predicting increased PTSD risk resulting from alcohol abuse.